The present invention relates to methods for the preparation of sidechain-bearing taxanes and intermediates thereof, and to the novel compounds prepared by these methods.
Taxanes are diterpene compounds which find utility in the pharmaceutical field. For example, taxol, a taxane having the structure: 
where Ph is phenyl, Ac is acetyl and Bz is benzoyl, has been found to be an effective anticancer agent. Naturally occurring taxanes such as taxol may be found in plant materials, and have been isolated therefrom. Such taxanes may, however, be present in plant materials in relatively small amounts so that, in the case of taxol, for example, large numbers of the slow-growing yew trees forming a source for the compound may be required. The art has thus continued to search for synthetic, including semi-synthetic routes for the preparation of taxanes such as taxol and analogs thereof, as well as routes for the preparation of intermediates used in the preparation of these compounds.
The present invention provides a novel, overall method for the preparation of novel sidechain-bearing taxanes, comprising the following steps (a) through (e):
(a) preparing an oxazoline compound of the following formula I or a salt thereof: 
xe2x80x83where
R1 is R5, R7xe2x80x94Oxe2x80x94, R7xe2x80x94Sxe2x80x94, or (R5)(R6)Nxe2x80x94;
R2 is R7xe2x80x94Oxe2x80x94, R7xe2x80x94Sxe2x80x94, or (R5)(R6)Nxe2x80x94;
R3 and R4 are independently R5, R5xe2x80x94Oxe2x80x94C(O)xe2x80x94, or (R5)(R6)Nxe2x80x94C(O)xe2x80x94;
R5 and R6 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclo; and
R7 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclo;
(b) converting the oxazoline of formula I or salt thereof to an oxazoline of the formula II or a salt thereof: 
xe2x80x83where R1, R3 and R4 are as defined above;
(c) coupling the oxazoline of the formula II or salt thereof with a taxane having a hydroxyl group directly bonded to C-13 thereof, or salt thereof, to form an oxazoline sidechain-bearing taxane of the following formula III or a salt thereof: 
xe2x80x83where R1, R3 and R4 are as defined above, and T is a taxane moiety preferably a compound of Formula IX bonded directly through C-13 of said moiety;
(d) contacting the oxazoline sidechain-bearing taxane of the formula III or salt thereof with an aqueous acid capable of opening the oxazoline ring of said compound of the formula III or salt thereof to form a sidechain-bearing taxane of the following formula X or salt thereof: 
xe2x80x83where R1, R3, R4 and T are as defined above, and the acid salt at the amine group in said formula X is formed by contact with said ring-opening acid; and
(e) contacting said sidechain-bearing taxane of the formula X or salt thereof with a base to form a sidechain-bearing taxane of the following formula IV or salt thereof: 
xe2x80x83where R1, R3, R4 and T are as defined above.
In addition, the present invention provides the individual methods of each of steps (a) through (e) which are novel methods, and the novel compounds of the formulae I, II, III, IV, IX and X and salts and hydrates thereof as described following. Also included are novel prodrugs of these compounds.
The present invention is described further as follows.
The terms xe2x80x9calkylxe2x80x9d or xe2x80x9calkxe2x80x9d, as used herein alone or as part of another group, denote optionally substituted, straight and branched chain saturated hydrocarbon groups, preferably having 1 to 10 carbons in the normal chain, most preferably lower alkyl groups. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Exemplary substituents may include one or more of the following groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g., to form a benzyl group), cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (xe2x80x94COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH2xe2x80x94COxe2x80x94), substituted carbamoyl ((R5)(R6)Nxe2x80x94COxe2x80x94 where R5 or R6 are as defined above, except that at least one of R5 or R6 is not hydrogen), amino (xe2x80x94NH2), heterocyclo, mono- or dialkylamino, or thiol (xe2x80x94SH).
The terms xe2x80x9clower alkxe2x80x9d or xe2x80x9clower alkylxe2x80x9d as used herein, denote such optionally substituted groups as described above for alkyl having 1 to 4 carbon atoms in the normal chain.
The terms xe2x80x9calkoxyxe2x80x9d or xe2x80x9calkylthioxe2x80x9d denote an alkyl group as described above bonded through an oxygen linkage (xe2x80x94Oxe2x80x94) or a sulfur linkage (xe2x80x94Sxe2x80x94), respectively. The term xe2x80x9calkyloxycarbonylxe2x80x9d, as used herein, denotes an alkoxy group bonded through a carbonyl group. The term xe2x80x9calkylcarbonylxe2x80x9d, as used herein, denotes an alkyl group bonded through a carbonyl group. The term xe2x80x9calkylcarbonyloxyxe2x80x9d, as used herein, denotes an alkyl group bonded through a carbonyl group which is, in turn, bonded through an oxygen linkage. The terms xe2x80x9cmonoalkylaminoxe2x80x9d or xe2x80x9cdialkylaminoxe2x80x9d denote an amino group substituted by one or two alkyl groups as described above, respectively.
The term xe2x80x9calkenylxe2x80x9d, as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon double bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include ethenyl, propenyl, isobutenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, and the like. Exemplary substituents may include one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (xe2x80x94COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH2xe2x80x94COxe2x80x94), substituted carbamoyl ((R5)(R6)Nxe2x80x94COxe2x80x94 where R5 or R6 are as defined above, except that at least one of R5 or R6 is not hydrogen), amino (xe2x80x94NH2), heterocyclo, mono- or dialkylamino, or thiol (xe2x80x94SH).
The term xe2x80x9calkynylxe2x80x9d, as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon triple bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Exemplary substituents may include one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (xe2x80x94COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH2xe2x80x94COxe2x80x94), substituted carbamoyl ((R5)(R6)Nxe2x80x94COxe2x80x94 where R5 or R6 are as defined above, except that at least one of R5 or R6 is not hydrogen), amino (xe2x80x94NH2), heterocyclo, mono- or dialkylamino, or thiol (xe2x80x94SH).
The term xe2x80x9ccycloalkylxe2x80x9d, as used herein alone or as part of another group, denotes optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring. Exemplary unsubstituted such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl. Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The term xe2x80x9ccycloalkenylxe2x80x9d, as used herein alone or as part of another group, denotes such optionally substituted groups as described above for cycloalkyl, further containing at least one carbon to carbon double bond forming a partially unsaturated ring.
The terms xe2x80x9carxe2x80x9d or xe2x80x9carylxe2x80x9d, as used herein alone or as part of another group, denote optionally substituted, homocyclic aromatic groups, preferably containing 1 or 2 rings and 6 to 12 ring carbons. Exemplary unsubstituted such groups include phenyl, biphenyl, and naphthyl. Exemplary substituents include one or more, preferably three or fewer, nitro groups, alkyl groups as described above or groups described above as alkyl substituents.
The terms xe2x80x9cheterocycloxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d, as used herein alone or as part of another group, denote optionally substituted fully saturated or unsaturated, aromatic or non-aromatic cyclic groups having at least one heteroatom in at least one ring, preferably monocyclic or bicyclic groups having 5 or 6 atoms in each ring. The heterocyclo group may, for example, have 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring. Each heterocyclo group may be bonded through any carbon or heteroatom of the ring system. Exemplary heterocyclo groups include the following: thienyl, furyl, pyrrolyl, pyridyl, imidazolyl, pyrrolidinyl, piperidinyl, azepinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, and benzofurazanyl. Exemplary substituents include one or more alkyl groups as described above or one or more groups described above as alkyl substituents. Also included are smaller heterocyclos, such as, epoxides and aziridines.
The terms xe2x80x9chalogenxe2x80x9d, xe2x80x9chaloxe2x80x9d, or xe2x80x9chalxe2x80x9d, as used herein alone or as part of another group, denote chlorine, bromine, fluorine, and iodine.
The term xe2x80x9ctaxane moietyxe2x80x9d, as used herein, denotes moieties containing the core structure: 
which core structure may be substituted and which may contain ethylenic unsaturation in the ring system thereof.
The term xe2x80x9ctaxanexe2x80x9d, as used herein, denotes compounds containing a taxane moiety as described above.
The term xe2x80x9chydroxy (or hydroxyl) protecting groupxe2x80x9d, as used herein, denotes any group capable of protecting a free hydroxyl group which, subsequent to the reaction for which it is employed, may be removed without destroying the remainder of the molecule. Such groups, and the synthesis thereof, may be found in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by T. W. Greene, John Wiley and Sons, 1991, or Fieser and Fieser. Exemplary hydroxyl protecting groups include methoxymethyl, 1-ethoxyethyl, 1-methoxy-1-methylethyl, benzyloxymethyl, (xcex2-trimethylsilylethoxy)methyl, tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl, t-butyl(diphenyl)silyl, trialkylsilyl, trichloromethoxycarbonyl, and 2,2,2-trichloroethoxymethyl.
The term xe2x80x9csaltxe2x80x9d includes acidic and/or basic salts formed with inorganic and/or organic acids and bases. Exemplary acidic salts include salts formed with mineral acids such as HCl, H2SO4, or HNO3, or carboxylic acids such as trifluoroacetic acid or acetic acid. Exemplary basic salts include salts formed with amines such as triethylamine, diisopropylethylamine, or pyridine or amino acids such as arginine, or guanidine. Salts of hydroxyl groups, such as metal (e.g., alkali or alkaline earth metal) alkoxides, are also contemplated as xe2x80x9csaltsxe2x80x9d herein. Metal alkoxide salts may, for example, be formed by contacting a hydroxyl group with a metallating agent.
Reference to a compound employed in or prepared by the methods of the present invention includes salts and hydrates thereof, unless otherwise indicated.
The present invention provides novel methods for the preparation of oxazoline compounds of the formula I and salts thereof, in particular, the dehydration, displacement, and exchange methods described following.
The present invention also provides the novel oxazoline compounds of the formula I and salts thereof, including all stereoisomers thereof, either substantially free of other stereoisomers, or in admixture with other selected, or all other stereoisomers, with the provisos that, when R1 is phenyl and one of R3 or R4 is hydrogen, (i) R2 is not methoxy when the other of R3 or R4 is pentadecyl, benzyl, or methoxycarbonyl, or (ii) R2 is not ethoxy when the other of R3 or R4 is ethoxycarbonyl; when R1 is methyl and one of R3 or R4 is hydrogen, R2 is not 8-phenylmenthyloxy when the other of R3 or R4 is 2-methylpropyl; and when R1 is acetylmethyl and R3 and R4 are hydrogen, R2 is not ethoxy or NH2.
Oxazolines of the formula Ia and salts thereof described following are preferred, especially compounds of the formula Ia having those substituents set forth in the section below entitled xe2x80x9cPreferred Compoundsxe2x80x9d.
Oxazoline compounds of the formula I or salts thereof may be prepared by a dehydration method, comprising the step of contacting a compound of the following formula V or a salt thereof: 
where R1, R2, R3 and R4 are as defined above, with an acid capable of effecting dehydration of the compound of formula V or salt thereof to form a compound of the formula I or salt thereof.
The starting compounds of the formula V and salts thereof may be prepared by procedures such as those described in U.S. patent application Ser. No. 07/975,453, filed Nov. 12, 1992 by Patel et al.; Ojima et al., J. Org. Chem., 56, 1681-1683 (1991); Georg et al., Tetrahedron Lett., 32, 3151-3154 (1991); Denis et al., J. Org. Chem., 51, 46-50 (1986); Corey et al., Tetrahedron Lett., 32, 2857-2860 (1991); Deng et al., J. Org. Chem., 57, 4320-4323 (1992); Ojima et al., Tetrahedron, 48, 6985-7012 (1992); Commercon et al., Tett. Lett., 33, 5185-5188 (1992); Denis et al., J. Org. Chem., 56(24), 6939-6942 (1991) (for example, followed by esterification and treatment with acid); and Denis et al., J. Org. Chem., 55, 1957-1959 (1990), all incorporated herein by reference.
Any acid capable of effecting dehydration may be employed in the dehydration method of the present invention. Exemplary acids include sulfonic acids such as pyridinium p-toluene sulfonic acid, p-toluene sulfonic acid, camphorsulfonic acid, and methane sulfonic acid, carboxylic acids such as trifluoroacetic acid or acetic acid, or mineral acids such as HCl, H2SO4 or HNO3. Mole ratios of acid: compound of formula V are preferably from about 1:100 to about 1:1.
The reaction is preferably conducted at a temperature of from about 0xc2x0 C. to about 200xc2x0 C., and at a pressure of about 1 atm to about 5 atm. The reaction is preferably conducted under an atmosphere of inert gas such as argon.
Solvents are preferably employed which are inert, organic solvents such as toluene, tetrahydrofuran, acetonitrile, benzene or xylene. The amount of solvent employed preferably provides a loading of the starting compound of formula V of about 2.5% by weight, based on the combined weight of solvent and formula V compound.
The oxazoline ring of the compounds of the formula I is numbered herein as follows: 
With respect to the 4- and 5-position carbon atoms, the oxazoline compounds of the formula I may exist as four stereoisomers Ia, Ib, Ic and Id as follows: 
The compounds of the formula V may also exist as four stereoisomers, with respect to the carbon atoms at the corresponding positions. These stereoisomers are the following compounds Va, Vb, Vc and Vd: 
A desired stereoisomer of the compound of the formula I may, for example, be prepared by the present dehydration method by employing the appropriate stereoisomer of the starting compound of the formula V. Thus, use of a compound Va will provide a compound Ia, use of a compound Vb will provide a compound Id, use of a compound Vc will provide a compound Ic, and use of a compound Vd will provide a compound Ib. It is preferred to employ a single stereoisomer of the starting compound V in the present dehydration method, although stereoisomeric mixtures may also be employed. Use of a compound Va to prepare a compound Ia, especially to prepare a compound Ia having those substituents set forth in the section below entitled xe2x80x9cPreferred Compoundsxe2x80x9d, is particularly preferred.
Oxazoline compounds of the formula I or salts thereof may also be prepared by a displacement method, comprising the step of contacting a compound of the formula V or salt thereof, in the presence of a base, with an activating agent capable of activating the hydroxyl group of the compound of the formula V or salt thereof to allow intramolecular displacement and formation of a compound of the formula I or salt thereof, with the proviso that, when R1 is phenyl, and one of R3 or R4 is hydrogen, (i) R2 is not ethoxy when the other of R3 or R4 is ethoxycarbonyl, or (ii) R2 is not methoxy when the other of R3 or R4 is benzyl.
Any compound capable of activating the hydroxyl group of the compound of the formula V and effecting intramolecular displacement may be employed as the activating agent in the displacement method of the present invention. Exemplary activating agents include sulfonyl halides such as alkyl sulfonyl halides (e.g., methyl sulfonyl chloride), or aryl sulfonyl halides (e.g., benzene sulfonyl chloride or p-toluenesulfonyl chloride), phosphorus oxychloride (POCl3), phosphorus pentachloride (PCl5), or thionyl chloride (SOCl2). Mole ratios of activating agent: compound of formula V are preferably from about 1:1 to about 2:1.
Activation of the hydroxyl group of a compound of the formula V or salt thereof may produce a novel intermediate compound of the formula VI or salt thereof: 
where R1, R2, R3 and R4 are as defined above, and L is a leaving group such as alkyl sulfonyloxy (e.g., methyl sulfonyloxy), aryl sulfonyloxy (e.g., benzene sulfonyloxy or p-toluenesulfonyloxy), chloro, or a phosphorus oxy group (PO2xe2x80x94 or POxe2x80x94). The present invention provides the aforementioned novel compounds of the formula VI and salts thereof, including all stereoisomers thereof, either substantially free of other stereoisomers, or in admixture with other selected, or all other stereoisomers, with the proviso that, when R1 is phenyl, R2 is methoxy and one of R3 or R4 is hydrogen and the other benzyl, L is not chloro.
Bases which may be employed include organic bases such as amines (e.g., pyridine, triethylamine, diisopropylethylamine, lutidine, or 1,8-diazabicyclo[5.4.0]undec-7-ene), or lithium hexamethyl disilazide, or inorganic bases such as alkali metal carbonates (e.g., potassium carbonate). Mole ratios of base: compound of formula V are preferably greater than about 2:1.
The reaction is preferably conducted at a temperature of from about xe2x88x9220xc2x0 C. to about 100xc2x0 C., particularly 0xc2x0 C., and at a pressure of about 1 atm. The reaction is preferably conducted under an atmosphere of inert gas such as argon.
Solvents are preferably employed which are inert organic solvents such as chloroform, methylene chloride, toluene, tetrahydrofuran, acetonitrile or, most preferably, which are basic organic solvents capable of functioning both as solvent and as base for the present method such as pyridine, triethylamine, or lutidine. The amount of solvent employed preferably provides a loading of the starting compound of the formula V of about 10% by weight, based on the combined weight of solvent and formula V compound.
A desired stereoisomer of the compound of the formula I may, for example, be prepared by the present displacement method by employing the appropriate stereoisomer of the starting compound of the formula V. Thus, use of a compound Va will provide a compound Ic, use of a compound Vb will provide a compound Ib, use of a compound Vc will provide a compound Ia, and use of a compound Vd will provide a compound Id. It is preferred to employ a single stereoisomer of the starting compound V in the present displacement method, although stereoisomeric mixtures may also be employed. Use of a compound Vc to form a compound Ia, especially to prepare a compound Ia having those substituents set forth in the section below entitled xe2x80x9cPreferred Compoundsxe2x80x9d, is particularly preferred.
Oxazoline compounds of the formula I where R1 is R1xe2x80x2 as defined following or salts thereof may also be prepared by an exchange method, comprising the step of contacting a compound of the following formula VII or a salt thereof: 
where R2, R3 and R4 are as defined above, with a compound of the following formula VIII or salt thereof: 
where R1xe2x80x2 and E are independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclo;
with the provisos that, when E is ethyl, one of R3 or R4 is hydrogen, and (i) R1xe2x80x2 is phenyl, R2 is not methoxy when the other of R3 or R4 is methoxycarbonyl, and R2 is not ethoxy when the other of R3 or R4 is ethoxycarbonyl; and (ii) R1xe2x80x2 is methyl, R2 is not 8-phenylmenthyloxy when the other of R3 or R4 is 2-methylpropyl.
When both starting compounds VII and VIII are simultaneously employed as acid salts at the NH2 and HN groups, respectively, an amine base, such as ammonia or an organic amine base, may be employed to form a free NH2 and/or HN group, respectively, to allow the reaction to proceed efficiently. Any amine base capable of forming the free NH2 and/or HN group(s) may be employed therein. Tertiary amine bases such as triethylamine, diisopropylethylamine, lutidine, pyridine or 1,8-diazabicyclo[5.4.0]undec-7-ene are preferred. Mole ratios of amine base: compound of formula VII are preferably from about 1:1 to about 10:1.
The starting compounds of the formula VII and salts thereof may be prepared by methods such as those described in U.S. patent application Ser. No. 07/975,453, filed Nov. 12, 1992 by Patel et al.; Commercon et al., Tetrahedron Lett., 33 (36), 5185-5188 (1992); Corey et al., Tetrahedron Lett., 32, 2857-2860 (1991); Ojima et al., Tetrahedron, 48, 6985-7012 (1992); and Ojima et al., Tetrahedron Lett., 33, 5737-5740 (1992), all incorporated herein by reference. The starting compounds of the formula VII and salts thereof may be prepared by methods such as those described in Kimball et al., Org. Synth. Coll. Vol. 11, p. 284 (1943). Use of acidic salts of compounds of the formula VIII, for example. salts formed with carboxylic, sulfonic or mineral acids, are preferably employed as starting materials, as such compounds are relatively stable and easily handled. The aforementioned salts may be neutralized upon contact with the base employed as discussed above. Mole ratios of compound of formula VIII: compound of formula VII are preferably from about 1:1 to about 2:1.
The reaction is preferably conducted at a temperature of from about 0xc2x0 C. to about 100xc2x0 C., and at a pressure of about 1 atm. The reaction is preferably conducted under an inert atmosphere, such as argon or nitrogen.
Solvents are preferably employed which are inert organic solvents such as toluene, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, or chloroform. The amount of solvent employed preferably provides a loading of the starting compound of the formula VII of about 6% by weight, based on the combined weight of solvent and formula VII compound.
The compounds of the formula VII may, as with the compounds of the formula V, exist as four stereoisomers with respect to the carbon atoms at the corresponding positions. These stereoisomers are the following compounds VIIa, VIIb, VIIc and VIId: 
A desired stereoisomer of the compound of the formula I may, for example, be prepared by the present exchange method by employing the appropriate stereoisomer of the starting compound of the formula VII. Thus, use of a compound VIIa will provide a compound Ia, use of a compound VIIb will provide a compound Id, use of a compound VIIc will provide a compound Ic, and use of a compound VIId will provide a compound Ib. It is preferred to employ a single stereoisomer of the starting compound VII in the present exchange method, although stereoisomeric mixtures may also be employed. Use of a compound VIIa to prepare a compound Ia, especially to prepare a compound Ia having those substituents set forth in the section below entitled xe2x80x9cPreferred Compoundsxe2x80x9d, is particularly preferred.
Oxazoline compounds of the formula II and salts thereof may be prepared from oxazoline compounds of the formula I and salts thereof by converting the group xe2x80x94C(O)xe2x80x94R2 to the group xe2x80x94C(O)xe2x80x94OH.
Any agent capable of the aforementioned conversion may be employed. For example, when R2 is alkoxy such as methoxy or ethoxy, the compound of the formula I or salt thereof may be dealkylated to form a compound of the formula II by use of a suitable nucleophilic agent, such as the alkali or alkaline earth metal salts of methanethiol. Alternatively, hydrogenation may be employed, for example, to convert groups such as benzyloxycarbonyl to carboxyl, by use of a hydrogenating agent, for example, hydrogen and a hydrogenation catalyst such as palladium.
Preferably, conversion of the group xe2x80x94C(O)xe2x80x94R2 to a carboxyl group is conducted by hydrolysis. Any compound capable of effecting hydrolysis may be employed as the hydrolysis agent therein. Exemplary hydrolysis agents include aqueous bases such as hydroxides (e.g., metal hydroxides such as barium hydroxide, or preferably, alkali metal hydroxides such as lithium, sodium or potassium hydroxide). Mole ratios of base: compound of formula I are preferably from about 1:1 to about 3:1. Mole ratios of water: compound of formula I are preferably from about 1:1 to about 100:1.
The reaction is preferably conducted at a temperature of from about xe2x88x9220xc2x0 C. to about 100xc2x0 C., and at a pressure of about 1 atm. Hydroxide saponification of compounds of the formula I or salts thereof where R2 is xe2x80x94N(R5)(R6) is preferably conducted at the higher temperatures of the aforementioned temperature range, or at temperatures approaching or at the reflux temperature of the liquid medium employed. The reaction is preferably conducted under an atmosphere of nitrogen, argon or air.
Solvents may be selected from inorganic and organic liquids such as water, alcohols, toluene, tetrahydrofuran, dioxane, acetonitrile, or dimethylformamide, or mixtures thereof. A mixture of water and an organic liquid such as tetrahydrofuran is preferably employed as solvent. The amount of solvent employed preferably provides a loading of the starting compound of the formula I of about 7% by weight, based on the combined weight of solvent and formula I compound.
The present invention also provides the novel compounds of the formula II and salts thereof, including all stereoisomers thereof, either substantially free of other stereoisomers, or in admixture with other selected, or all other stereoisomers, with the proviso that, when R1 is phenyl and one of R3 or R4 is hydrogen, the other of R3 or R4 is not COOH. As with the oxazolines of the formula I, the oxazolines of the formula II may exist as four stereoisomers with respect to the 4- and 5-position carbon atoms. These stereoisomers are the following compounds IIa, IIb, IIc and IId: 
Oxazolines of the formula IIa and salts thereof are preferred, especially compounds of the formula IIa having those substituents set forth in the section below entitled xe2x80x9cPreferred Compoundsxe2x80x9d.
The stereoconfiguration of the starting compound of the formula I or salt thereof may be retained and/or inverted in the present method. Thus, for example, hydrolysis of a compound of the formula I having substituents which are in the cis position relative to each other at the 4- and 5-positions may be hydrolyzed to provide a compound of the formula II having the corresponding cis configuration, a compound of the formula II having the corresponding trans configuration where the 5-position carboxyl substituent is inverted relative to the starting compound, or a mixture of the aforementioned cis and trans compounds. Bases which, when employed for hydrolysis, deprotonate the carbon atom through which the group xe2x80x94C(O)xe2x80x94R2 is bonded, and which subsequently reprotonate the aforementioned carbon from the opposite face of the ring system, result in inversion of the stereoconfiguration. Exemplary such bases include those described above or alkali metal carbonates such as potassium carbonate, amine bases, or metal, such as alkali or alkaline earth metal, alkoxides, the latter which may be formed prior to addition thereof or in situ (for example, by addition of a metallating agent such as n-butyllithium together with an alkanol such as ethanol).
Where the stereoconfiguration is inverted during the present method as described above, a compound of the formula I having an inverted stereoconfiguration relative to the starting compound of the formula I may be formed as an intermediate (i.e., epimerization). Thus, for example, where the starting compound of the formula I has substituents at the 4- and 5-positions which are in the cis position relative to each other, the corresponding trans compound of the formula I where the 5-position substituent xe2x80x94C(O)xe2x80x94R2 is inverted relative to the starting compound may be formed as in intermediate during the hydrolysis reaction. The aforementioned inversion method is also contemplated within the scope of the present invention.
A sidechain-bearing taxane of the formula III or a salt thereof may be prepared by a method comprising the step of contacting an oxazoline compound of the formula II or a salt thereof, with a taxane having a hydroxyl group directly bonded to C-13 thereof, or a salt thereof, in the presence of a coupling agent. It is preferred to employ oxazolines of the formula IIa or salts thereof in the present method, especially compounds of the formula IIa having those substituents set forth in the section below entitled xe2x80x9cPreferred Compoundsxe2x80x9d.
Taxanes are compounds containing the core structure: 
which core structure may be substituted and which may contain ethylenic unsaturation in the ring system thereof, as described above. Any taxane containing a hydroxyl group directly bonded to C-13 thereof, or salt thereof (such as a metal alkoxide salt at the C-13 hydroxyl group) may be employed in the present method. The taxane starting material employed in the method of the present invention may be a compound such as those described in European Patent Publication No. 400,971, incorporated herein by reference, or may be a compound containing a taxane moiety described in, and prepared by procedures described in or analogous to those set forth in, U.S. patent application Ser. No. 07/907,261, filed Jul. 1, 1992 by Chen et al., or in U.S. patent application Ser. No. 07/981,151, filed Nov. 24, 1992 by Ueda et al., both incorporated herein by reference. Exemplary such taxanes include those of the following formula IX: 
where
R8 is hydrogen, hydroxyl, R14xe2x80x94Oxe2x80x94, R15xe2x80x94C(O)xe2x80x94Oxe2x80x94, or R15xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94;
R9 is hydrogen, hydroxyl, fluoro, R14xe2x80x94Oxe2x80x94, R15xe2x80x94C(O)xe2x80x94Oxe2x80x94 or R15xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94;
R10 and R11 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, R16xe2x80x94Oxe2x80x94, aryl, or heterocyclo;
R14 is a hydroxyl protecting group; and
R15 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclo,
R16 is alkyl
or salts thereof.
All stereoconfigurations of the unspecified chiral centers of the compound of the formula IX are contemplated for use in the coupling method of the present invention. The use of a single stereoisomer is preferred, although mixtures thereof may be employed. 7-Trialkylsilyl baccatin III compounds are one of the compounds preferably employed as the starting material of formula IX, most preferably, 7-trimethylsilyl baccatin III or 7-triethylsilyl baccatin III.
Another series of compounds which are preferable starting materials of formula IX are compounds wherein R8 is OC(O)CH3; R9 is hydroxyl or a hydroxyl protecting group e.g. O-trimethylsilyl or O-triethylsilyl; R10 is as above except methyl and R11 is aryl e.g. benzyl. The latter compounds are considered novel along with methods for their preparation which are set forth below. Especially preferred of the above compounds are those wherein R10 is cycloalkyl or OR16.
The above compounds are prepared by the following general reaction scheme 
Step F
Baccatin III is protected at the C-7 and C-13 sites by reaction with a suitable agent, such as, a halotrialkylsilane e.g. trimethyl or triethyl, 2,2,2-trichloroethyl chloroformate or carbobenzyloxy. Any inert organic solvent wherein Baccatin III is soluble may be utilized, such as, THF, DMF, MeCl2 and dioxane. The reaction is carried out in the presence of a tertiary amine base, such as, pyridine or imidazole. The reaction temperature can vary from xe2x88x9230xc2x0 C. to room temperature with C-7 substitution occuring preferably at xe2x88x9230xc2x0 C. to 0xc2x0 C. and C-13 at 0xc2x0 C. to room temperature. The protecting group reactant concentration is preferably in molar excess (1-10) to effect both C-7 and C-13 substitution.
Step G
The intermediate XI is thereafter protected at the C-1 hydroxy by reaction with a trimethylsilane or preferably a dimethylsilane e.g. chlorotrimethylsilane or preferably chlorodimethylsilane in, for example, DMF, THF, dioxane or various ethers. As in step F the reaction is preferably carried out in the presence of a tertiary amine base, such as imidazole or pyridine. The temperature can range from xe2x88x9230xc2x0 C. to room temperature with about 0xc2x0 C. as preferred.
Step H
(A) Intermediate XII is thereafter reduced at C-4 to hydroxy by reaction with a suitable reducing agent such as Red-Al or lithium aluminum hydride. The reducing agent is usually present in molar excess (1-5 equivalents). The reaction solvent can be THF, dioxane or various suitable ethers and the reaction temperature can range from xe2x88x9230xc2x0 C. to 0xc2x0 C. with about 0xc2x0 C. as preferred.
(B) Intermediate XIII of (A) wherein C-4 is hydroxy is converted to the appropriate C-4 substituent by reaction with the appropriate acyl chloride acid anhydride or mixed anhydride e.g. acryloyl chloride, benzoyl chloride, cycloalkylcarbonyl chloride, alkyl chloroformate, in the presence of an alkali metal (Li, Na or K) anion of a secondary amine base. The reaction solvents include THF, dioxane, etc. The temperature range can be from xe2x88x9230xc2x0 C. to room temperature with about 0xc2x0 C. as preferred.
Step I
(A) The intermediate XIII of step H (B) is thereafter deprotected by reaction with pyridinium fluoride (aqueous hydrogen fluoride in pyridine) in acetonitrile followed by tetrabutylammonium fluoride in THF or cesium fluoride in THF. Thereafter the mixture is diluted in an alcohol, washed with mild organic or inorganic acid and isolated.
(B) Thereafter the C-7 hydroxy protecting group may be introduced in XIV as in Step F following reaction parameters favoring C-7 substitution above.
Subsequently, the appropriate side chain may be introduced at C-13 following the novel process disclosed herein or alternatively via Holton methodology as disclosed in U.S. Pat. Nos. 5,227,400, 5,175,315 and 5,229,526 which are herein incorporated by reference.
As novel end products of the present invention therefore are compounds of the formula 
where
R1 is R5, R7xe2x80x94Oxe2x80x94, R7xe2x80x94Sxe2x80x94, or (R5)(R6)Nxe2x80x94;
R3 and R4 are independently R5, R5xe2x80x94Oxe2x80x94C(O)xe2x80x94, or (R5)(R6)Nxe2x80x94C(O)xe2x80x94;
R5 and R6 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclo; and
R7 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclo;
and T is 
xe2x80x83where
R8 is hydrogen, hydroxyl, R14xe2x80x94Oxe2x80x94, R15xe2x80x94Cxe2x80x94(O)xe2x80x94Oxe2x80x94, or R15xe2x80x94Oxe2x80x94C (O)Oxe2x80x94;
R9 is hydrogen, hydroxyl, fluoro, R14xe2x80x94Oxe2x80x94, R15xe2x80x94C(O)xe2x80x94Oxe2x80x94 or R15xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94;
R10 and R11 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, R16xe2x80x94O-aryl, or heterocyclo;
R14 is a hydroxyl protecting group; and
R15 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclo,
R16 is alkyl with the proviso that R10 is not methyl
or salts or hydrates thereof.
Especially preferred among the novel compounds of formula IV are those compounds wherein R10 is cycloalkyl or OR16. Most preferred among the novel compound of formula IV are compounds wherein R10 is cycloalkyl, R1 is aryl, preferably phenyl, or alkoxy preferably t-butyloxy; R3 is aryl, preferably phenyl, heterocyclo preferably 2- or 3-furanyl or thienyl, isobutenyl, 2-propenyl, isopropyl or (CH3)2CHxe2x80x94; R4 is hydrogen; R8 is preferably hydroxyl or alkylcarbonyloxy, e.g. acetyloxy; R9 is hydroxy and R11 is aryl, preferably phenyl.
Any compound capable of effecting esterification of the C-13 hydroxyl group, or salt thereof, of the starting taxane through the carboxyl group of the oxazoline of the formula II or salt thereof may be employed as the coupling agent of the present method. Exemplary coupling agents include those compounds forming an activated oxazoline ester (for example, 1-hydroxybenzotriazole or N-hydroxysuccinimide) or anhydride (for example, an acid chloride such as pivaloyl chloride or bis(2-oxo-3-oxazolidinyl)-phosphinic chloride) when contacted with the oxazoline of the formula II, particularly coupling agents comprising a compound such as a carbodiimide (e.g., dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide (DIC), or 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride), bis(2-oxo-3-oxazolidinyl)phosphinic chloride), carbonyl diimidazole (CDI), pivaloyl chloride, or 2,4,6-trichlorobenzoyl chloride; wherein the aforementioned compounds are preferably employed together with a compound such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOxe2x80x94Su), or an amine such as triethylamine, pyridine or pyridine substituted at the 4-position with xe2x80x94N(R16)(R17), where R16 and R17 are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or heterocyclo (to form a compound such as 4-dimethylaminopyridine (DMAP)), or where R16 and R17, together with the nitrogen atom to which they are bonded, form a heterocyclo group (to form a compound such as 4-morpholinopyridine or 4-pyrrolidinopyridine). Mole ratios of coupling agent: starting taxane are preferably from about 1:1 to about 2:1. Mole ratios of oxazoline of the formula II: starting taxane are preferably from about 1:1 to about 2:1.
The reaction is preferably conducted at a temperature of from about 0xc2x0 C. to about 140xc2x0 C., and at a pressure of about 1 atm. The reaction is preferably conducted under an atmosphere of inert gas such as argon.
Solvents are preferably employed which are inert organic liquids such as toluene, acetonitrile, 1,2-dichloroethane, chloroform, tetrahydrofuran, pyridine, methylene chloride or dimethylformamide. The amount of solvent employed preferably provides a loading of the starting taxane of about 20% by weight, based on the combined weight of solvent and taxane compound.
The stereoconfiguration of the substituents at the 4- and 5-positions of the starting oxazoline may be retained and/or inverted in the coupled formula III product, for example, epimerization from cis to trans where the 5-position substituent has been inverted relative to the starting material is contemplated.
The present invention also provides the novel oxazoline sidechain-bearing taxanes of the formula III and salts thereof, including all stereoisomers thereof, either substantially free of other stereoisomers, or in admixture with other selected, or all other stereoisomers.
A sidechain-bearing taxane of the formula X or a salt thereof may be prepared from an oxazoline sidechain-bearing taxane of the formula III or a salt thereof, by a method comprising the step of contacting a taxane of the formula III or salt thereof with an aqueous acid capable of opening the ring of the oxazoline group bonded through C-13 of the taxane moiety of said taxane compound to form said compound of the formula X or salt thereof.
Any aqueous acid capable of effecting the aforementioned ring opening may be employed in the method of the present invention. Exemplary ring opening acids include carboxylic acids, such as acetic acid or trifluoroacetic acid, or preferably, mineral acids such as hydrochloric acid, hydrofluoric acid or sulfuric acid, in water. Mole ratios of ring opening acid: compound of formula III are preferably from about 1:1 to about 10:1. Mole ratios of water: compound of formula III are preferably from about 1:1 to about 100:1.
The ring opening reaction is preferably conducted at a temperature of from about xe2x88x9220xc2x0 C. to about 40xc2x0 C., and at a pressure of about 1 atm. The reaction is preferably conducted under an atmosphere of nitrogen, argon or air.
Solvents are preferably employed which are inert organic liquids alone or in admixture with water such as tetrahydrofuran, alcohols (preferably, lower alkanols such as methanol), dioxane, toluene, acetonitrile, or mixtures thereof. The amount of solvent employed preferably provides a loading of the starting compound of the formula III of about 5% by weight, based on the combined weight of solvent and formula III compound.
A preferred embodiment of the present invention further comprises the step of deprotecting one or more groups, particularly to free hydroxyl groups, on the taxane moiety to prepare taxanes of the formula X. Deprotection may, for example, be conducted prior or subsequent to, or simultaneously with, the aforementioned ring opening method by use of a deprotection agent. Any compound capable of deprotection may be employed as the deprotection agent. For example, acids such as hydrofluoric acid or aqueous protic acids, or tetra-alkylammonium fluorides such as tetra-n-butylammonium fluoride, may be employed for removal of silyl protecting groups; benzyl protecting groups may be removed by hydrogenation; trichloroethoxycarbonyl protecting groups may be removed by contact with zinc; and acetal or ketal protecting groups may be removed by the use of protic acids or Lewis acids.
A preferred embodiment of the present invention comprises simultaneous ring opening and deprotection of one or more hydroxyl groups on the taxane ring structure, particularly at C-7. A particularly preferred embodiment comprises the step of simultaneous ring opening and deprotection by use of an acid (e.g., a mineral acid such as hydrochloric acid) capable of effecting both reactions. Thus, for example, use of an acid under reaction conditions described above for ring opening may allow simultaneous ring opening and deprotection of acid cleavable hydroxyl protecting groups at C-7 such as trialkylsilyl (e.g. trimethylsilyl or triethylsilyl).
The present invention also provides the novel intermediates of the formula X and salts thereof formed during ring opening and, optionally, deprotection, including all stereoisomers thereof, either substantially free of other stereoisomers, or in admixture with other selected, or all other stereoisomers.
Treatment of a compound of the formula X or salt thereof with a base provides a compound of the formula IV or salt thereof. Any base allowing migration of the acyl group xe2x80x94C(O)xe2x80x94R1 to the amine group xe2x80x94NH2, thereby effecting formation of a compound of the formula IV or salt thereof, may be employed in the method of the present invention. Exemplary bases include alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate. Mole ratios of base: compound of formula X are preferably from about 1:1 to about 5:1.
The reaction is preferably conducted at a temperature of from about xe2x88x9220xc2x0 C. to about 80xc2x0 C., and at a pressure of 1 atm. The reaction is preferably conducted under an atmosphere of argon, nitrogen or air.
Solvents are preferably employed which are inert organic liquids alone or in admixture with water such as tetrahydrofuran, alcohols (preferably, lower alkanols such as methanol), toluene, acetonitrile, dioxane, or mixtures thereof. The amount of solvent employed preferably provides a loading of the compound of the formula X of from about 1 to about 5% by weight, based on the combined weight of solvent and formula X compound.
Deprotection of protected groups may be conducted simultaneously with, or subsequent to use of a base, although deprotection prior to contact with a base, especially simultaneously with ring opening, is preferably employed, as described above.
The products of the methods of the present invention may be isolated and purified, for example, by methods such as extraction, distillation, crystallization, and column chromatography.
The sidechain-bearing taxanes of the formula IV and salts thereof prepared by the methods of the present invention are themselves pharmacologically active. or are compounds which may be converted to pharmacologically active products. Pharmaco-logically active taxanes such as taxol may be used as antitumor agents to treat patients suffering from cancers such as breast, ovarian, colon or lung cancers, melanoma or leukemia. The utility of such sidechain-bearing taxanes has been described, for example, in European Patent Publication No. 400,971, U.S. Pat. Nos. 4,876,399, 4,857,653, 4,814,470, 4,924,012, 4,924,011,U.S. patent application Ser. No. 07/907,261, filed Jul. 1, 1992 by Chen et al., and U.S. patent application Ser. No. 07/981,151, filed Nov. 24, 1992 by Ueda et al., all incorporated herein by reference.
Taxotere, having the structure shown following, or especially taxol, having the structure shown above, are preferably ultimately prepared as the sidechain-bearing taxanes of the formula IV: 
Solvates, such as hydrates, of reactants or products may be employed or prepared as appropriate in any of the methods of the present invention.
Also considered within the ambit of the present invention are the water soluble prodrug forms of the compounds of formula IV. Such prodrug forms of the compounds of formula IV are produced by introducing at C-7 or C-10 and/or at the 2xe2x80x2-position of the side chain a phosphonoxy group of the general formula
xe2x80x94OCH2(OCH2)mOP(O)(OH)2
wherein m is 0 or an integer from 1 to 6 inclusive.
The novel prodrugs have the formula 
where
R1 is R5, R7xe2x80x94Oxe2x80x94, R7xe2x80x94Sxe2x80x94, or (R5) (R6)Nxe2x80x94;
R3 and R4 are independently R5, R5xe2x80x94Oxe2x80x94C(O)xe2x80x94, or (R5)(R6)Nxe2x80x94C(O)xe2x80x94;
R5 and R6 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclo; and
R7 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclo;
and T is 
xe2x80x83where
R8 is hydrogen, hydroxyl, R14xe2x80x94Oxe2x80x94, R15xe2x80x94C(O)xe2x80x94Oxe2x80x94, R15xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94, or xe2x80x94OCH2(OCH2)mOP(O)(OH)2;
R10 and R11 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, R16xe2x80x94Oxe2x80x94, aryl or heterocyclo;
R20 is hydrogen, xe2x80x94OCH2(OCH2)mOP(O)(OH)2, xe2x80x94OC(O)R21 or xe2x80x94OC(O)OR21 wherein R21 is C1-C6 alkyl optionally substituted with one to six halogen atoms, C3-C6 cycloalkyl, C2-C6 alkenyl or a radical of the formula 
xe2x80x83wherein D is a bond or C1-C6 alkyl and Ra, Rb and Rc are independently hydrogen, amino, C1-C6 mono- or di-alkylamino, halogen, C1-C6 alkyl or C1-C6 alkoxy;
R14 is a hydroxy protecting group;
R16 is alkyl;
R30 is hydrogen, hydroxy, fluoro, xe2x80x94OCH2(OCH2)mOP(O)(OH)2 or xe2x80x94OC(O)OR21 wherein R21 is as above.
R15 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclo;
m is 0 or an integer from 1 to 6 inclusive with the proviso that at least one of R8, R20 and R30 is xe2x80x94OCH2(OCH2)mOP(O)(OH)2 and R10 is not methyl
and phosphonxy group base salts thereof.
Preferred compounds of formula IVxe2x80x2 include those wherein R10 is cycloalkyl or OME or OEt; R1 is aryl, preferably phenyl or alkoxy preferably t-butyloxy; R3 is aryl preferably phenyl or heterocyclo, preferably furyl or thienyl or alkenyl preferably propenyl or isobutenyl; R4 is hydrogen; R8 is hydroxy or alkylcarbonyloxy, preferably acetyloxy; R11 is aryl preferably phenyl; R20 is xe2x80x94OCH2(OCH2)mOP(O)(OH)2 or xe2x80x94OC(O)OR21 wherein R21 is ethyl or N-propyl; R30 is xe2x80x94OCH2(OCH2)mOP(O)(OH)2 and m is 0 or 1.
The phosphonoxy group is normally introduced following synthesis of the end products of formula IV following procedures set forth in U.S. Ser. No. 08/108,015 filed Aug. 17, 1993 which is incorporated by reference herein.
In arriving at the novel prodrugs above, various novel intermediates are formed following the reaction conditions set forth generally in U.S. Ser. No. 08/108,015. Compounds of formula IV are used as starting materials wherein non-desired hydroxy groups have been blocked. The appropriately protected compound of formula IV wherein reactive hydroxy groups are present either at the 2xe2x80x2 or 7 or 10 positions or at multiple positions is first connected to a corresponding methylthiomethyl ether [xe2x80x94OCH2(OCH2)mSCH3]. Thereafter depending on the value of m, the ether may be connected to a protected phosphonooxymethyl ether by a variety of steps as set forth in the above U.S. Ser. No. The phosphono protecting group(s) and the hydroxy protecting groups may thereafter be removed by conventional techniques.
The free acid can then be converted to the desired base salt thereafter by conventional techniques involving contacting the free acid with a metal base or with an amine. Suitable metal bases include hydroxides, carbonates and bicarbonates of sodium, potassium, lithium, calcium, barium, magnesium, zinc, and aluminum; and suitable amines include triethylamine, ammonia, lysine, arginine, N-methylglucamine, ethanolamine, procaine, benzathine, dibenzylamine, tromethamine (TRIS), chloroprocaine, choline, diethanolamine, triethanolamine and the like. The base salts may be further purified by chromatography followed by lyophilization or crystallization.
The prodrugs may be administered either orally or parenterally following the teaching of the above patent application (08/108,015). The compounds of Formula IV and IVxe2x80x2 are novel antitumor agents showing in vitro cytotoxicity activity against human colon carcinoma cell lines HCT-116 and HCT-116/VM46and M109lung carcinoma.
The present invention is further described by the following examples which are illustrative only, and are in no way intended to limit the scope of the instant claims.